Methods and composition of 4-substituted benzoylpiperazine-1-substituted carbonyls as beta-catenin/B-cell lymphoma 9 inhibitors

Abstract

In one aspect, the invention relates to 4-substituted benzoylpiperazine-1-substituted carbonyls having a structure represented by a formula: derivatives thereof, and related compounds; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with β-catenin/BCL9 protein-protein interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
       1. A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein A is —N— or —CR 8 —;
 wherein R 8  is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 
         wherein L 1  is optionally present, and when present, is O, S, or NH; 
         wherein L 2  is optionally present, and when present, is O, S, NR 9 , or —(CR 10a R 10b ) n —,
 wherein n is an integer having the value of 1, 2, or 3; 
 wherein R 9  is hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 wherein each occurrence of R 10a  and R 10b  is independently hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
 
         wherein each of R 1a  and R 1b  is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl; 
         wherein each of R 2a , R 2b , and R 2c  is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl; 
         wherein R 3  is Cy 3  or Ar 1 ;
 wherein Cy 3  is a C3-C8 cycloalkyl or a C2-C7 heterocycloalkyl; and wherein Cy 3  is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H; 
 wherein Ar 1  is selected from aryl and heteroaryl, and wherein Ar 1  is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H; 
 
         wherein R 4  is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl; 
         wherein each occurrence of R 5  is independently selected from hydrogen, unsubstituted C1-C8 alkyl, C1-C8 monohaloalkyl, or C1-C8 polyhaloalkyl; 
         wherein R 6  is C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 1 ; and wherein Cy 1  is a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein R 7  is H 2 N—(C1-C6 alkyl)-(C═O)—; HO—(C1-C6 alkyl)-(C═O)—; C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 2 ; and wherein Cy 2  is a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom; and wherein Cy 2  is substituted 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound of  claim 1 , wherein L 2  is not present. 
     
     
       3. The compound of  claim 1 , wherein Cy 2  has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         and wherein R 10  is hydrogen, methyl, ethyl, propyl, or isopropyl. 
       
     
     
       4. The compound of  claim 1 , wherein each of R 1a , R 1b , R 2a , R 2b , and R 2c  is hydrogen. 
     
     
       5. The compound of  claim 1 , wherein R 3  is phenyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H. 
     
     
       6. The compound of  claim 1 , wherein R 3  is cyclohexyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H. 
     
     
       7. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is cyclohexyl or phenyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H; wherein R 4  is —F, —Br, methyl, ethyl, —CFH 2 , —CF 2 H, or —CF 3 ; wherein R 10  is hydrogen, methyl, ethyl, propyl, or isopropyl; and wherein R 11  is hydrogen, methyl, ethyl, propyl, or isopropyl. 
       
     
     
       8. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.